Difluorothioacetamides of oxazolidinones as antibacterial agents

ABSTRACT

The present invention describes difluororthioacetamide oxazolidinones as novel antibacterial agents, and antimicrobial combination therapies for combating infective diseases caused by gram-positive and gram-negative bacteria.

CROSS REFERENCE

[0001] This application claims the benefit of the following provisionalapplication: U.S. Serial No. 60/392,213, filed Jun. 28, 2002, under 35USC 119(e)(i), which is incorporated herein by reference in itsentirety.

FILED OF THE INVENTION

[0002] The present invention describes difluororthioacetamideoxazolidinones as novel antibacterial agents, and antimicrobialcombination therapies for combating infective diseases caused bygram-positive and gram-negative bacteria.

BACKGROUND OF THE INVENTION

[0003] The thioamide oxazolidinone antibacterial agents are a novelsynthetic class of antimicrobials with broad activity against a numberof human and veterinary pathogens, including gram-positive aerobicbacteria such as multiply-resistant staphylococci and streptococci,gram-negative aerobic bacteria such as H. influenzae and M. catarrahlis,as well as anaerobic organisms such as bacteroides and clostridiaspecies, and acid-fast organisms such as Mycobacterium tuberculosis andMycobacterium aviur.

[0004] As a chemical compound class, thioamide oxazolidinones generallyare rapidly metabolized. It is known in the pharmaceutical filed thatcompounds with minimum metabolism are preferred to rapidly metabolizedcompounds for several reasons. It is easier to maintain therapeuticblood levels of slowly metabolized compounds (active ingredients) sincethey typically have lower clearance than rapidly metabolized compounds.Blood levels in humans are more predictable for slowly metabolizedcompounds since there is no effect from normal human variability inenzyme levels and activity. Metabolized compounds may also generatetoxic metabolites, whereas non-metabolized compounds do not.

[0005] Accordingly, there is a demand to discover thioamideoxazolidinone antibacterial agents that possess minimum metabolism.Difluorothioacetamide oxazolidinones of the present invention havepotent activity against gram-positive human and veterinary pathogens. Inparticular, it is unexpectedly discovered that these compounds have goodstability in vivo and a very low metabolism rate.

INFORMATION DISCLOSURE

[0006] U.S. Pat. No. 6,342,513 discloses Oxazolidinone antibacterialagents having a thiocarbonyl functionality.

[0007] U.S. Pat. No. 6,281,210 discloses Benzoic acid esters ofoxazolidinones having a hydroxyacetylpiperazine substituent.

[0008] U.S. Pat. No. 6,166,056 discloses phenyloxazolidinones having aC—C bond to 4-6 membered heterocyclic rings.

[0009] International publication WO 01/58885 discloses oxazolidinonethioamides with piperazine amide substituents.

[0010] International Publication WO 01/46185 discloses oxazolidinoneshaving a sulfoximine functionality.

SUMMARY OF THE INVENTION

[0011] The present invention provides a novel oxazolidinone compound offormula I

[0012] or pharmaceutically acceptable salt wherein

[0013] R is —CH₂— or —CH₂CH₂—;

[0014] R² and R³ are independently —H or —F;

[0015] X is —N— or —CH—;

[0016] Y is —SO—, —SO₂—, or —SONR⁴—; and R⁴ is —H or —C₁₋₄alkyl.

[0017] The present invention further provides a method for treatinggram-positive bacterial infections which comprises administration to amammal being treated a pharmaceutically effective amount of the compoundof formula I, either individually, or in combination with othergram-positive antibiotics.

[0018] The present invention further provides a method for treatinggram-positive and gram-negative bacterial infections which comprisesadministration to a mammal being treated a pharmaceutically effectiveamount of the compound of formula I in combination with at least oneother gram-negative antibiotic.

[0019] The present invention further provides compositions for treatinggram-positive bacterial infections wherein the compositions comprise apharmaceutically effective amount of the compound of formula I and atleast one other gram-positive antibiotic.

[0020] The present invention further provides compositions for treatinggram-positive and gram-negative bacterial infections wherein thecompositions comprise a pharmaceutically effective amount of thecompound of formula I and at least one other gram-negative antibiotic.

[0021] The present invention further provides methods of preparation ofthe compounds of formula I of the present invention.

[0022] The present invention further provides a use of the compound offormula I to prepare a medicament, for treating gram-positive and/orgram-negative bacterial infections.

DETAILED DESCRIPTION OF THE INVENTION

[0023] Definitions

[0024] The term “antibiotic” refers to an antibacterial agent other thanthe compound of the present invention.

[0025] Specifically, they refer to Amikacin, Gentamicin, Spectinomycin,Tobramycin, Imipenem, Meropenem, Cefadroxil, Cefazolin, Cephalexin,Cefaclor, Cefotetan, Cefoxitin, Cefprozil, Cefuroxime, Loracarbef,Cefdinir, Cefixime, Cefoperazone, Cefotaxime, Cefpodoxime, Ceftazidime,Ceftibuten, Ceftozoxime, Ceftriaxone, Cefepime, Azithromycin,Clarithromycin, Dirithromycin, Penicillin G, Cloxacillin, Dicloxacillin,Nafcillin, Oxacillin, Amoxicillin, Amoxicillin, Ampicillin, Mezlocillin,Piperacillin, Nalidixic Acid, Ciprofloxacin, Enoxacin, Lomefloxacin,Norfloxacin, Ofloxacin, Levofloxacin, Sparfloxacin, Alatrofloxacin,Gatifloxacin, Moxifloxacin, Trimethoprim, Sulfisoxazole,Sulfamethoxazole, Doxycycline, Minocycline, Tetracycline, Aztreonam,Chloramphenicol, Clindamycin, Quinupristin, Fosfomycin, Metronidazole,Nitrofurantoin, Rifampin, Trimethoprim, and Vancomycin. All of them areknown. They can be either obtained commercially or be prepared accordingto the references cited in PHYSICIANS' DESK REFERENCE, the 53^(rd)Edition (1999) and the US FDA's Orange book.

[0026] The term “gram-positive antibiotic” refers to an antibacterialagent active against gram-positive bacterial organisms.

[0027] The term “gram-negative antibiotic” refers to an antibacterialagent active against gram-negative bacterial organisms. For the purposeof the present invention, the carbon atom content of varioushydrocarbon-containing moieties is indicated by a prefix designating theminimum and maximum number of carbon atoms in the moiety, i.e., theprefix C_(i-j) indicates a moiety of the integer “i” to the integer “j”carbon atoms, inclusive. Thus, the term “C₁₋₄alkyl refers to alkyl ofone to four carbon atoms, inclusive, or methyl, ethyl, propyl, andbutyl, straight and branched forms thereof.

[0028] Specifically, R² and R³ are H.

[0029] Specifically, R² and R³ are F.

[0030] Specifically, R² is H and R³ is F.

[0031] Specifically, R² is F and R³ is H.

[0032] Specifically, R is —CH₂—.

[0033] Specifically, R is —CH₂CH₂—.

[0034] Specifically, X is N.

[0035] Specifically X is CH.

[0036] Specifically Y is —SO—, or —SO₂—.

[0037] Specifically Y is —SO(NH)—.

[0038] Specifically Y is —SO(NCH₃)—.

[0039] Specifically Y is —SO(NHC₁₋₄alkyl)—.

[0040] Specifically, the formula I is the formula Ia or Ib shown below.

[0041] Specifically, the formula I is the formula Ic or Id shown below.

[0042] Examples of the present invention are:

[0043] (1)2,2-difluoro-N-[((5S)-3-{3-fluoro-4-[1-(methylimino)-1-oxido-1λ⁴,4-thiazinan-4-yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]ethanethioamide,

[0044] (2)2,2-difluoro-N-({(5S—)-3-[3-fluoro-4-(1-imino-1-oxidohexahydro-1λ⁴-thiopyran-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide(Z-(isomer),

[0045] (3)2,2-difluoro-N-({(5S)-3-[3-fluoro-4-(1-imino-1-oxidohexahydro-1λ⁴-thiopyran-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide(E-isomer),

[0046] (4)2,2-difluoro-N-({(5S)-3-[3-fluoro-4-(1-methylimino-1-oxidohexahydro-1λ⁴-thiopyran-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide(Z-isomer),

[0047] (5)2,2-difluoro-N-({(5S)-3-[3-fluoro-4-(1-methylimino-1-oxidohexahydro-1λ⁴-thiopyran-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide(E-isomer),

[0048] (6)2,2-difluoro-N-({(5S)-3-[4-(1,1-dioxidothiomorpholin-4-yl)-3-fluorophenyl]2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide,

[0049] (7)2,2-difluoro-N-({(5S)-3-[4-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-3fluorophenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide,

[0050] (8)2,2-difluoro-N-({(5S)-3-[3-fluoro-4-(1-oxidotetrahydro-2H-thiopyran-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide(Z-Isomer),

[0051] (9)2,2-difluoro-N-({(5S)-3-[3-fluoro-4-(1-oxidothiomorpholin-5-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide,

[0052] (10)2,2-difluoro-N-({(5S)-3-[4-(1,1-dioxido-1,4-thiazepan-4-yl)-3-fluorophenyl]2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide,

[0053] (11)2,2-difluoro-N-({(5S)-3-[4-(1,1-dioxido-1,4-thiazepan-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide,

[0054] (12)2,2-difluoro-N-({(5S)-3-[4-(1,1-dioxidothiomorpholin-4-yl)-3,5-difluorophenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide,

[0055] (13)2,2-difluoro-N-({(5S)-3-[4-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide,

[0056] (14)2,2-difluoro-N-({(5S)-3-[3,5-difluoro-4-(1-oxidothiomorpholin-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide,

[0057] (15)2,2-difluoro-N-({(5S-3-[4-(1,1-dioxido-1,4-thiazepan-4-yl)-3,5-difluorophenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide,

[0058] (16)2,2-difluoro-N-({(5S)-3-[4-(1,1-dioxidothiomorpholin-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide,

[0059] (17)2,2-difluoro-N-({(5S)-3-[4-(1-oxidothiomorpholin-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide,

[0060] (18) 2,2-difluoro-N-({(5S)-3-[3-fluoro-4-(1-imino-1-oxido-1λ⁴,4-thiazinan-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide,

[0061] (19)2,2-difluoro-N-({(5S)-3-[3-fluoro-4-(1-oxido-1,4-thiazepan-4-yl)phenyl]-220oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide,

[0062] (20) 2,2-difluoro-N-({(5S)-3-[4-(1-imino-1-oxido-1λ⁴,4-thiazinan-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide,

[0063] (21) 2,2-difluoro-N-(((5S)-3-{4-[1-(methylimino)-1-oxido-1λ⁴,4-thiazinan-4-yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]ethanethioamide,

[0064] (22)2,2-difluoro-N-({(5S)-3-[3-fluoro-4-(1-oxidotetrahydro-2H-thiopyran-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide(E-Isomer),

[0065] (23)2,2-difluoro-N-({(5S)-3-[4-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)phenyl]2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide,

[0066] (24)2,2-difluoro-N-({(5S)-3-[4-(1-oxidotetrahydro-2H-thiopyran-4-yl)phenyl]-230oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide (Z-isomer),

[0067] (25)2,2-difluoro-N-({(5S)-3-[3,5-difluoro-4-(1-oxidotetrahydro-2H-thiopyran-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide(E-isomer),

[0068] (26)2,2-difluoro-N-({(5S)-3-[4-(1-oxidotetrahydro-2H-thiopyran-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide(E-isomer),

[0069] (27)2,2-difluoro-N-({(5S)-3-[3,5-difluoro-4-(1-oxidotetrahydro-2H-thiopyran-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide(Z-isomer),

[0070] (28)2,2-difluoro-N-({(5S)-3-[4-(1-imino-1-oxidohexahydro-1λ⁴-thiopyran-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide(Z-isomer),

[0071] (29)2,2-difluoro-N-({(5S)-3-[4-(1-imino-1-oxidohexahydro-1λ⁴-thiopyran-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide(E-isomer),

[0072] (30)2,2-difluoro-N-({(5S)-3-[4-(1-methylimino-1-oxidohexahydro-1λ⁴-thiopyran-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide(Z-isomer), and

[0073] (31)2,2-difluoro-N-({(₅S)-3-[4-(1-methylimino-1-oxidohexahydro-1λ⁴-thiopyran-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide(E-isomer).

DESCRIPTIONS FOR THE PREPARATION

[0074] Compounds of formula I are prepared as illustrated in Schemes Iand II. As shown in Scheme I compounds of formula I are convenientlyprepared by allowing compounds of formula II to react with an ester ofdifluoroethanethioic O-acid (III) where R⁵ is C₁₋₄ alkyl, optionallysubstituted by one or two phenyl groups. Suitable solvents for thisreaction include methanol, chloroform, methylene chloride or mixturesthereof at temperatures of about 10° C. to about 30° C. A tertiary aminebase can be used to facilitate this reaction, especially if a salt ofthe amine (II) is employed.

[0075] Alternatively, a compound of formula I can be obtained byreacting a compound of formula II withO-(3,3-diphenylpropyl)difuoroethanethioate in protic or aprotic polarsolvents (such as methanol, acetonitrile, dioxane, methylene cloride(CH₂Cl₂), N,N-dimethylformamide, dimethylsulfoxide or alike, or mixturesthereof) in presence of an optional organic or inorganic base (such astriethylamine, pyridine, or potassium carbonate). The process can beconducted in the range of temperatures of 5-100° C., preferably, at20-75° C.

[0076] A second method for the preparation of compounds of formula I(wherein Y′ is —SO₂—, or —SONR⁴—) is shown in Scheme II. In this methodcompounds of formula II′ are condensed with difluoroacetic acid to givecompounds of formula IV. Reagents and conditions for this condensationinclude the use of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (EDC) with 4-(dimethylamino)pyridine (DMAP) in pyridine atabout 0° C. to about 25° C.; or EDC with 1-hydroxybenzotriazole hydrate(HOBT) and triethylamine in DMF at 0° C. to 25° C. Compounds of formulaIV are then allowed to react with Lawesson's Reagent in dioxane attemperatures of about 50° C. to about 100° C. to give compounds offormula I′.

EXAMPLES Example 1 Preparation of2,2-difluoro-N-[((5S)-3-{3-fluoro-4-[1-(methylimino)-1-oxido-1λ⁴,4-thiazinan-4-yl]phenyl}-2-oxo-1,3-oxazolidin-5 yl)methyl]ethanethioamide (1).

[0077] Step 1. Preparation of(5S)-5-(aminomethyl)-3-{3-fluoro-4-[1-(methylimino)1-oxido-1λ⁴,4-thiazinan-4-yl]phenyl}-1,3-oxazolidin-2-one (3).

[0078] A stirred solution of 2 (prepared according to the proceduredescribed in International Publication WO 01/46185) (100 mg, 0.25 mmol)in MeOH (7 ml) is treated with water (1 ml) and concentratedhydrochloric acid (1 ml), refluxed for 17 hours and concentrated invacuo. A mixture of the residue and brine is adjusted to pH 11 withsodium hydroxide and extracted with 5% MeOH—CH₂Cl₂. The extracts aredried (Na₂SO₄) and concentrated. Flash chromatography of the residue onsilica gel with 10% MeOH-0.05% NH₄OH—CHCl₃ gave the title compound (3).MS (ESI+) m/z 357 (M+H⁺); MS (ESI−) m/z 391 (M+Cl).

[0079] Step 2. Preparation of2,2-difluoro-N-[((5S)-3-{3-fluoro-4-[1-(methylimino)1-oxido-1λ⁴,4-thiazinan-4-yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide(4).

[0080] A stirred mixture of 3 (518 mg, 1.45 mmol), difluoroacetic acid(107 μL, 1.74 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (EDC) (340 mg, 1.77 mmol), 4-(dimethylamino)pyridine(DMAP) (18 mg, 0.15 mmol) and pyridine (10 ml) is kept, under nitrogenat ambient temperature (24° C.) for 24 hours, treated with additionaldifluoroacetic acid (107 μL) and EDC (350 mg) and stirred for about 96hours. It is diluted with MeOH and concentrated in vacuo. A mixture ofthe residue and brine is adjusted to pH 11 with 1N NaOH and extractedwith 5% MeOH-CH₂Cl₂. The extract is dried (NaSO₄) and concentrated.Flash chromatography of the residue on silica gel with 3% MeOH—CH₂Cl₂gave the title compound (4). MS (ESI+) m/z 435 (M+H⁺); MS (ESI−) m/z 433(M−H), 469 (M+Cl); HRMS (ESI) calcd for C₁₇H₂₂F₃N₄O₄S (M+H⁺) 435.1313,found 435.1325

[0081] Step 3. Preparation of2,2-difluoro-N-[((5S)-3-{3-fluoro-4-[1-(methylimino)-1-oxido-1λ⁴,4-thiazinan-4-yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]ethanethioamide(1).

[0082] A stirred solution of 4 (324 mg, 0.746 mmol) in dioxane (10 ml)is treated, portionwise during 10 min, with Lawesson's Reagent (336 mg,0.831 mmol) and refluxed, under nitrogen, for 2 hours. It is cooled,diluted with MeOH and CH₂Cl₂ and a concentrated in vacuo. A solution ofthe residue in CH₂Cl₂ is extracted first with 3N HCl and then with 1NHCl. The combined aqueous extract is neutralized to pH 6-7, concentratedin vacuo to about 150 ml, adjusted to pH 11-12 with 50% NaOH andextracted with 5% MeOH—CH₂Cl₂. The extract is dried (Na₂SO₄) andconcentrated. Flash chromatography of the residue on silica gel with1-2% MeOH-CH₂Cl₂ gave the title compound (1).

[0083] Physical data: MS (ESI+) m/z 451 (M+H⁺), 473 (M+Na⁺).

[0084] MS (ESI−) m/z 449 (M−H).

[0085] HRMS (FAB) calcd for C₁₇H₂₂F₃N₄O₃S₂ (M+H⁺) 451.1085, found451.1075.

Example 2 Preparation of 2,2-difluoro-N-({(5S—)-3-[3-fluoro-4-(1-imino-1oxidohexahydro-1λ⁴-thiopyran-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide,Z-isomer (5).

[0086]

[0087] A stirred suspension of 6 (prepared according to the proceduredescribed in International Publication WO 01/46185) (0.54 g, 1.23 mmol)in MeOH (5 ml) is treated dropwise with a solution ofO-(3,3-diphenylpropyl)difuoroethanethioate 7 (0.43 g, 1.40 mmol) inCH₂Cl₂ (5 ml) and the resulting pale yellow solution is kept at ambienttemperature (24° C.) for 40 min and concentrated in vacuo. Flashchromatography of the residue on silica gel with 3% MeOH—CHCl₃ andcrystallization of the product from MeOH gave the title compound (5).

[0088] Physical data: mp 212-213° C. (dec).

[0089] MS (ESI+) m/z 436 (M+H⁺).

[0090] MS (ESI−) m/z 434 (M−H).

[0091] Anal. Calcd for C₁₇H₂₀F₃N₃O₃S₂: C, 46.89: H, 4.63; N, 9.65.Found: C, 46.89;

[0092] H, 4.65; N, 9.61.

Method for Preparing O-(3,3-diphenylpropyl)difuoroethanethioate 7

[0093]

[0094] To a stirred solution of difluoroacetic acid (5.00 g, 52.1 mmol)and 3,3-diphenyl-1-propanol (11.4 ml, 57.3 mmol, 1.10 eq) in diethylether (100 ml) is added 4-dimethylaminopyridine (0.64 g, 5.21 mmol, 0.01eq) followed by diisopropylcarbodiimide (6.56 g, 52.1 mmol, 1.0 eq). Themixture is stirred at room temperature overnight. The precipitate isremoved by vacuum filtration and washed with ether and the filtrateconcentrated in vacuo. The residue is filtered through a plug of silicagel using 5% ether/hexanes eluent and the filtrate collected andconcentrated. The resulting compound (14.40 g, 46.64 mmol) in xylenes(150 ml) is added Lawesson's Reagent (24.1 g, 59.61 mmol). The reactionmixture is heated at reflux overnight and then cooled to roomtemperature. A precipitate formed which is removed by vacuum filtrationand washed with ethyl acetate. The filtrate is passed through a plug ofsilica gel and eluted with 5% ether/hexanes and concentrated to give thetitle compound 7. ¹H NMR (400 Mhz), CDCl₃) δ 2.47, 4.07, 4.24, 5.82,7.23.

EXAMPLE 3 Preparation of2,2-difluoro-N-({(5S)-3-[3-fluoro-4-(1-imino-1-oxidohexahydro-1λ⁴-thiopyran-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide,E-isomer (8).

[0095] Step 1. Preparation of(5S)-5-(aminomethyl)-3-[3-fluoro-4-(1-imino-1-oxidohexahydro-1λ⁴-thiopyran-4-yl)phenyl]-1,3-oxazolidin-2-one,E-isomer Hydrochloride (10).

[0096] A solution of 9 (prepared according to the procedure described inInternational Publication WO 01/46185) (1.02 g, 2.66 mmol) in MeOH (35ml) is treated with water (5 ml) and concentrated hydrochloric acid (5ml) and refluxed for 24 hours. The mixture is concentrated in vacuo togive the title compound (10) as solid.

[0097] Step 2. Preparation of2,2-difluoro-N-({(5S)-3-[3-fluoro-4-(1-imino-1-oxidohexahydro-1λ4-thiopyran-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide,E-isomer (8).

[0098] A stirred solution of 10 (0.55 g, 1.3 mmol), MeOH (7 ml), CH₂Cl₂(7 ml) and triethylamine (0.37 ml, 2.7 mmol) is treated, dropwise with asolution of 7 (0.46 g, 1.5 mmol) in 1 ml of MeOH: CH₂Cl₂ (1:1) andstirred, under nitrogen at ambient temperature (24° C.) for 1 hour. Itis then a concentrated in vacuo and the residue is flash chromatographedon silica gel with 3% MeOH—CHCl₃. Crystallization of the product fromMeOH gave the title compound (8)

[0099] Physical data: mp 190-191° C.

[0100] MS (ESI+) m/z 436 (M+H⁺).

[0101] MS (ESI−) m/z 434 (M−H).

[0102] Anal. Calcd for C₁₇H₂₀F₃N₃O₃S₂: C, 46.89; H, 4.63; N, 9.65.Found: C, 46.68; H, 4.64; N, 9.55.

Example 4 Preparation of2,2-difluoro-N-({(5S)-3-[3-fluoro-4-(1-methylimino-1-oxidohexahydro-1λ⁴-thiopyran-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide, Z-isomer (11).

[0103]

[0104] A stirred mixture of 5 (200 mg, 0.46 mmol) and paraformaldehyde(43 mg, 1.43 mmol) in CH₃CN (6 ml) is treated with trifluoroacetic acid(TFA) (142 μL, 1.83 mmol) and triethylsilane (220 μL, 1.38 mmol). It iskept at ambient temperature (24° C.), under nitrogen for 19 hours,diluted with brine and adjusted to pH 11 with 1 N NaOH. This mixture isextracted with 5% MeOH—CH₂Cl₂. The extract is dried (Na₂SO₄) andconcentrated in vacuo. Chromatography of the residue on silica gel with3% MeOH—CHCl₃ provides the title compound (11).

[0105] Physical data: MS (ESI+) m/z 450 (M+H⁺).

[0106] MS (ESI−) m/z 448 (M−H).

[0107] HRMS (FAB) calcd for C₁₈H₂₃F₃N₃O₃S₂ (M+H⁺) 450.1133, found450.1130.

EXAMPLE 5 Preparation of2,2-difluoro-N-({(5S)-3-[3-fluoro-4-(1-methylimino-1-oxidohexahydro-1λ⁴-thiopyran-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide,E-isomer (12).

[0108]

[0109] Following the procedure described in Example 4 for thepreparation of 11, the reaction of 8 with paraformaldehyde, TFA andtriethylsilane provides 12 which is purified by silica gelchromatography with 3.5% MeOH—CHCl₃.

[0110] Physical data: MS (ESI+) m/z 450 (M+H⁺).

[0111] MS (ESI−) m/z 448 (M−H).

[0112] HRMS (FAB) calcd for C₁₈H₂₃F₃N₃O₃S₂ (M+H⁺) 450.1133, found450.1134.

Example 6 Preparation of2,2-difluoro-N-({(5S)-3-[4-(1,1-dioxidothiomorpholin-4-yl)-3-fluorophenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide(13). 2672

[0113] Step 1. Preparation ofN-({(5S)-3-[4-(1,1-dioxidothiomorpholin-4-yl)-3-fluorophenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-2,2-difluoroacetamide(15).

[0114] An ice cold, stirred mixture of 14 (prepared according to theprocedure described in U.S. Pat. No. 6,342,523) (1.00 g, 2.91 mmol),HOBT (433 mg, 3.20 mmol) and difluoroacetic acid (0.275 ml, 4.37 mmol)in DMF (25 ml) is treated with EDC (1.23 g, 6.40 mmol) and kept in theice bath for 2 hours and at ambient temperature (24° C.) for 3 days. Itis concentrated in vacuo and the residue is stirred with water (80 ml)and filtered. The solid is washed with water and dried to give the titlecompound (15) as solid. A sample is chromatographed on silica gel with2.5% MeOH—CH₂Cl₂ and crystallized from MeOH: mp 177-178° C.; MS (EI) m/z421 (M⁺). Anal calcd for C₁₆H₁₈F₃N₃O₅S: C, 45.60; H, 4.30; N, 9.97.Found: C, 45.56; H, 4.31; N, 9.97.

[0115] Step 2. Preparation of2,2-difluoro-N-({(5S)-3-[4-(1,1-dioxidothiomorpholin-4-yl)-3-fluorophenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide(13).

[0116] Following the procedure described in Example 1 for thepreparation of 1 the reaction of 15 with Lawesson's Reagent provides thetitle compound (13), which is purified by silica gel chromatography with2.5% MeOH—CH₂Cl₂ and crystallization from EtOAc-hexane.

[0117] Physical data: mp 146-147° C.

[0118] MS (EI) m/z 437.1 (M⁺).

[0119] Anal calcd for C₁₆H₁₈F₃N₃O₄S₂: C, 43.93; H, 4.15; N, 9.60. Found:C, 43.79;

[0120] H, 4.15; N, 9.55.

EXAMPLE 7 Preparation of2,2-difluoro-N-({(5S)-3-[4-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-3-fluorophenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide(16).

[0121]

[0122] Following the procedure described in Example 6 for thepreparation of 13 the amine 17, (prepared according to the proceduredescribed in U.S. Pat. No. 6,342,523) is first condensed withdifluoroacetic acid and the resulting amide is allowed to react withLawesson's Reagent to give 16 which is purified by silica gelchromatography with 3% MeOH—CH₂Cl₂ and crystallization fromCH₂Cl₂-hexane.

[0123] Physical data: mp 168-169° C.

[0124] MS (EI) m/z 436 (M⁺).

[0125] Anal. calcd for C₁₇H₁₉F₃N₂O₄S₂: C, 46.78; H, 4.39; N, 6.42.Found: C, 46.85; H, 4.49; N, 6.32.

EXAMPLE 8 Preparation of2,2-difluoro-N-({(5S)-3-[3-fluoro-4-(1-oxidotetrahydro-2H-thiopyran-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide,Z-Isomer (18).

[0126]

[0127] A stirred solution of 19 (prepared according to the proceduredescribed in U.S. Pat. No. 6,342,523) (407.6 mg, 1.25 mmol) in CH₂Cl₂ (8ml) is treated with a solution of 7 (420.8 mg, 1.37 mmol) in CH₂Cl₂ (2ml) and kept at ambient temperature (24° C.) for 18 hours. It is thendiluted with CH₂Cl₂, washed with saturated NaHCO₃, water, and brine,dried (MgSO₄) and concentrated. Chromatography of the residue on silicagel with 2% MeOH—CH₂Cl₂ provides the title compound (18).

[0128] Physical data: mp 192-194° C.

[0129] Anal. calcd for C₁₇H₁₉F₃N₂O₃S₂: C, 48.56; H, 4.55; N, 6.66; S,15.25. Found: C, 48.56; H, 4.61; N, 6.57; S, 14.83.

EXAMPLE 9 Preparation of2,2-difluoro-N-({(5S)-3-[3-fluoro-4-(1-oxidothiomorpholin-5-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide(18).

[0130]

[0131] Following the procedure described in Example 8 for thepreparation of 18 the reaction of 21 (prepared according to theprocedure described in U.S. Pat. No. 6,342,523) with 7 provides thetitle compound 20.

[0132] Physical data: Anal. calcd for C₁₆H₁₈F₃N₃O₃S₂: C, 45.60; H, 4.30;N, 9.97.

[0133] Found: C, 45.73; H, 4.44; N, 9.74.

Example 10 Preparation of2,2-difluoro-N-({(5S)-3-[4-(1,1-dioxido-1,4-thiazepan-4-yl)-3-fluorophenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide(22).

[0134]

[0135] Following the procedure described in Example 3 for thepreparation of 8, a stirred mixture of the amine hydrochloride (23)(prepared according to the procedure described in U.S. Pat. No.6,342,523) and N,N-diisopropylethylamine in CH₂Cl₂ is allowed to reactwith 7 to give the title compound 22 which is purified by silica gelchromatography with 3% MeOH—CH₂Cl₂.

[0136] Physical data: mp 128-130° C.

[0137] Anal. calcd for C₁₇H₂₀F₃N₃O₄S₂: C, 45.22; H, 4.47; N, 9.31, S,14.20. Found:

[0138] C, 45.54; H, 4.53, N, 8.98; S, 13.69.

Example 11 Preparation of2,2-difluoro-N-({(5S)-3-[4-(1,1-dioxido-1,4-thiazepan-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide(24).

[0139]

[0140] Following the procedure described In Example 10 for thepreparation of 22, the reaction of 25 (prepared according to theprocedure described in U.S. Pat. No. 6,342,523) with 7 provides thetitle compound 24.

[0141] Physical data: Anal. calcd for C₁₇H₂₁F₂N₃O₄S₂: C, 47.10; H, 4.88;N, 9.69; S, 14.79. Found: C, 47.26; H, 5.12; N, 9.27; S, 14.14.

Example 12 Preparation of2,2-difluoro-N-({(5S)-3-[4-(1,1-dioxidothiomorpholin-4-yl)-3,5-difluorophenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide(26).

[0142]

[0143] Following the procedure described in Example 6 for thepreparation of 13 the amine 27 (prepared according to the proceduredescribed in U.S. Pat. No. 6,342,523) is first condensed withdifluoroacetic acid and the resulting amide is allowed to react withLawesson's Reagent to give the title compound 26 which is purified bysilica gel chromatography with 5% MeOH—CH₂Cl₂.

[0144] Physical data: mp 88-90° C.

[0145] HRMS (FAB) calcd for C₁₆H₁₈F₄N₃O₄S₂ (M+H⁺) 456.0675, found456.0671.

[0146] Anal. calcd for C₁₆H₁₇F₄N₃O₄S₂: C, 42.19; H, 3.76; N, 9.23.Found: C, 42.12; H, 3.93; N, 8.79.

EXAMPLE 13 Preparation of2,2-difluoro-N-({(5S)-3-[4-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide(28).

[0147]

[0148] Following the procedure described in Example 9 for thepreparation of 20 the reaction of 29 (prepared according to theprocedure described in U.S. Pat. No. 6,342,523) with 7 provides thetitle compound 28.

[0149] Physical data: mp 126-128° C.

[0150] MS m/z 455 (M+H⁺).

EXAMPLE 14 Preparation of2,2-difluoro-N-({(5S)-3-[3,5-difluoro-4-(1-oxidothiomorpholin-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide (30).

[0151]

[0152] Following the procedure described in Example 3 for thepreparation of 8, a mixture of 31 (prepared according to the proceduredescribed in U.S. Pat. No. 6,342,523) and triethylamine in CH₂Cl₂ isallowed to react with 7 to give the title compound 30 which is purifiedby silica gel chromatography with 2% MeOH—CH₂Cl₂.

[0153] Physical data:

[0154] HRMS calcd for C₁₆H₁₈F₄N₃O₃S₂ (M+H⁺) 440.0725, found 440.0724.

[0155] Anal. calcd for C₁₆H₁₇F₄N₃O₃S₂; C, 43.73; H, 3.90; N, 9.56.Found: C, 43.99; H, 4.15; N, 9.31.

Example 15 Preparation of2,2-difluoro-N-({(5S)-3-[4-(1,1-dioxido-1,4-thiazepan-4-yl)-3,5-difluorophenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide(32).

[0156]

[0157] Following the procedure described in Example 3 for thepreparation of 8, a mixture of 33 (prepared according to the proceduredescribed in U.S. Pat. No. 6,342,523) and triethylamine in CH₂Cl₂ isallowed to react with 7 to give the title compound 32 which is purifiedby silica gel chromatography with 3% MeOH—CH₂Cl₂.

[0158] Physical data:

[0159] HRMS calcd for C₁₇H₂₀F₄N₃O₄S₂ (M+H⁺) 470.0831, found 470.0844.

[0160] Anal. calcd for C₁₇H₁₉F₄N₃O₄S₂: C, 43.49; H, 4.08; N, 8.95.Found: C, 43.70; H, 4.17; N, 8.86.

Example 16 Preparation of2,2-difluoro-N-({(5S)-3-[4-(1,1-dioxidothiomorpholin-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide(34).

[0161]

[0162] Following the procedure described in Example 3 for thepreparation of 8, the amine 35 (prepared according to the proceduredescribed in U.S. Pat. No. 6,342,523) is first condensed withdifluoroacetic acid and the resulting amide is allowed to react withLawesson's Reagent to give 34 which is purified by silica gelchromatography with 2% MeOH—CH₂Cl₂ and crystallization fromEtOAc-CH₂Cl₂-hexane.

[0163] Physical data: mp 126-127° C.

[0164] MS (EI) m/z 419 (M+).

[0165] Anal. calcd for C₁₆H₁₉F₂N₃O₄S₂: C, 45.81; H, 4.57; N, 10.02.Found: C, 45.47; H, 4.53; N, 9.93.

EXAMPLE 17 Preparation of2,2-difluoro-N-({(5S)-3-[4-(1-oxidothiomorpholin-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide(36).

[0166]

[0167] Following the procedure described in Example 10 for thepreparation of 22, the reaction of 37 (prepared according to theprocedure described in U.S. Pat. No. 6,342,523) with 7 provides thetitle compound 36 which is crystallized from EtOAc-hexan.

[0168] Physical data: mp 155-156° C.

[0169] MS (EI) m/z 403.1 (M⁺).

[0170] Anal. calcd for C₁₆H₁₉F₂N₃O₂S₂: C, 47.63; H, 4.75; N, 10.41.Found: C, 47.64; H, 4.81; N, 10.31.

Example 18 Preparation of2,2-difluoro-N-({(5S)-3-[3-fluoro-4-(1-imino-1-oxido-1λ⁴,4-thiazinan-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide(38,).

[0171]

[0172] Following the procedure described in Example 14 for thepreparation of 30, the reaction of 39 (prepared according to theprocedure described in U.S. Pat. No. 6,342,523) and triethylamine inCH₂Cl₂ with 7 provides the title compound 38 which is purified by silicagel chromatography with 4% MeOH-0.5% NH₄OH—CHCl₃ and crystallizationfrom MeOH.

[0173] Physical data: mp 199.5-200.0° C.

[0174] MS (ESI+) m/z 437 (M+H⁺).

[0175] MS (ESI−) m/z 435 (M−H).

[0176] Anal. calcd for C₁₆H₁₉F₃N₄O₃S₂: C, 44.03; H, 4.39; N, 12.84.Found: C, 44.02; H, 4.51; N, 12.68.

Example 19 Preparation of2,2-difluoro-N-({(5S)-3-[3-fluoro-4-(1-oxido-1,4-thiazepan-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide(40)

[0177]

[0178] Following the procedure described in Example 10 for thepreparation of 22, the reaction of 41 (prepared according to theprocedure described in U.S. Pat. No. 6,342,523) with 7 provides 40 whichis purified by silica gel chromatography with 2.5% MeOH—CH₂Cl₂.

[0179] Physical data: Anal. calcd for C₁₇H₂₀F₃N₃S₂: C, 46.89; H, 4.63;N, 9.65; S, 14.72. Found: C, 46.29; H, 4.92; N, 9.08; S, 13.76.

Example 20 Preparation of2,2-difluoro-N-({(5S)-3-[4-(1-imino-1-oxido-1λ⁴,4-thiazinan-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide(42)

[0180] Step 1. Preparation ofN-({(5S)-3-[4-(1-oxidothiomorpholin-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide (44).

[0181] A stirred solution of 37 (prepared according to the proceduredescribed in U.S. Pat. No. 6,342,523) (674 mg, 2.18 mmol) in pyridine(37 ml) is treated with acetic anhydride (308 μL, 3.27 mmol), kept atambient temperature (about 24° C.) for 45 min and concentrated in vacuo.Chromatography of the residue on silica gel with 5% MeOH—CH₂Cl₂ andcrystallization of the product from EtOAc-hexane provides the titlecompound 44, as solid: mp 185-186° C.; MS (EI) m/z 351.2 (M⁺). Anal.calcd for C₁₆H₂₁N₃O₄S: C, 54.68; H, 6.02; N, 11.96. Found: C, 54.40; H,6.01; N, 11.77.

[0182] Step 2. Preparation of(5S)-5-(aminomethyl)-3-[4-(1-imino-1-oxido-1λ⁴,4-thiazinan-4-yl)phenyl]-1,3-oxazolidin-2-one hydrochloride (45).

[0183] As described in International Publication WO 01/46185), thereaction of 44 with sodium azide in polyphosphonic acid providesN-({(5S)-3-[4-(1-imino-1-oxido-1×4,4-thiazinan-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide (47,see Example 21) which is hydrolyzed with 6N HCl in MeOH as described inExample 3 for the preparation of 10 to give the title compound 45.

[0184] Step 3. Preparation of2,2-difluoro-N-({(5S)-3-[4-(1-imino-1-oxido-1λ⁴,4-thiazinan-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide(42).

[0185] Following the procedure described in Example 3, the reaction of45 with 7 provides 42 which is purified by silica gel chromatographywith 5% MeOH—CH₂Cl₂ and crystallization from MeOH-EtOAc.

[0186] Physical data: mp 182-183° C.

[0187] Anal calcd for C₁₆H₂₀F₂N₄O₃S₂: C, 45.92; H, 4.82; N, 13.39.Found: C, 45.43; H, 4.88; N, 13.23.

Example 21 Preparation of2,2-difluoro-N-(((5S)-3-{4-[1-(methylimino)-1-oxido-1λ⁴,4-thiazinan-4-yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]ethanethioamide(46).

[0188]

[0189] Following the procedure described in Example 4 for thepreparation of 11, the reaction of 47 (prepared according to theprocedure described in the International Publication WO 01/46185) withparaformaldehyde, triethylsilane and trifluoroacetic acid gaveN-({(5S)-3-[4-(1-methylimino-1-oxido-1λ⁴,4-thiazinan-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide (48)which is hydrolyzed with 6N HCl in MeOH. The reaction of the resultingproduct with 7 and triethylamine as described in Example 3 for thepreparation of 8 provides the title compound 46 which is purified bysilica gel chromatography with 5% MeOH—CH₂Cl₂ and crystallization fromEtOAc-MeOH-hexane.

[0190] Physical data: mp 147-148° C.

[0191] MS (EI) m/z 432 (M⁺).

[0192] Anal. calcd for C₁₇H₂₂F₂N₄O₃S₂: C, 47.21; H, 5.13; N, 12.95.Found: C, 47.23; H, 5.20; N, 12.97.

Example 22 Preparation of2,2-difluoro-N-({(5S)-3-[3-fluoro-4-(1-oxidotetrahydro-2H-thiopyran-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide,E-Isomer (49). PNU-280711

[0193]

[0194] Following the procedure described in Example 9 for thepreparation of 20, the reaction of 50 (prepared according to theprocedure described in U.S. Pat. No. 6,342,523) with 7 provides 49 whichis purified by silica gel chromatography with 3% MeOH—CH₂Cl₂.

[0195] Physical data: mp 192-194° C.

[0196] Anal. calcd for C₁₇H₁₉F₃N₂O₃S₂: C, 48.56; H, 4.55; N, 6.66; S,15.25. Found: C, 48.30; H, 4.58; N, 6.41; S, 14.73.

Example 23 Preparation of2,2-difluoro-N-({(5S)-3-[4-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide(51).

[0197]

[0198] Condensation of 52 (prepared according to the procedure describedin U.S. Pat. No. 6,342,523) with 7 and triethylamine in CH₂Cl₂ asdescribed in Example 3 for the preparation of 8 provides 51 which ispurified by silica gel chromatography with 2.5% MeOH—CHCl₃ andcrystallization from MeOH.

[0199] Physical data: mp 174-176° C.

[0200] Anal calcd for C₁₇H₂₀F₂N₂O₄S₂: C, 48.79; H, 4.82; N, 6.69. Found:C, 47.95;

[0201] H, 4.89; N, 6.43.

EXAMPLE 24 Preparation of2,2-difluoro-N-({(5S)-3-[4-(1-oxidotetrahydro-2H-thiopyran-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide,Z-isomer (53).

[0202]

[0203] Condensation of 54 (prepared according to the procedure describedin U.S. Pat. No. 6,342,523) with 7 and triethylamine in CH₂Cl₂ asdescribed in Example 3 for the preparation of 8 provides the titlecompound 53 which is purified by silica gel chromatography with 2.5%MeOH—CH₂Cl₂ and crystallization from MeOH.

[0204] Physical data: mp 216-217° C. (dec.).

[0205] Anal. calcd for C₁₇H₂₀F₂N₂O₃S₂: C, 50.73; H, 5.01; N, 6.96.Found: C, 50.75; H, 5.03; N, 6.96.

Example 25 Preparation of2,2-difluoro-N-({(5S)-3-[3,5-difluoro-4-(1-oxidotetrahydro-2H-thiopyran-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide,E-isomer (55).

[0206]

[0207] Condensation of 56 (prepared according to the procedure describedin U.S. Pat. No. 6,342,523) with 7 and triethylamine in CH₂Cl₂ asdescribed in Example 3 for the preparation of 8 provides the titlecompound 55.

[0208] Physical data: mp 102° C. (dec).

[0209] HRMS calcd for C₁₇H₁₉F₄N₂O₃S₂ (M+H⁺) 439.0773, found 439.0795.

[0210] Anal. calcd for C₁₇H₁₈F₄N₂O₃S₂: C, 46.57; H, 4.14; N, 6.39.Found: C, 46.12; H, 4.26; N, 5.69.

Example 26 Preparation of2,2-difluoro-N-({(5S)-3-[4-(1-oxidotetrahydro-2H-thiopyran-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide,E-isomer (57).

[0211]

[0212] Condensation of 58 (prepared according to the procedure describedin U.S. Pat. No. 6,342,523) with 7 and triethylamine in CH₂Cl₂ asdescribed in Example 3 for the preparation of 8 provides the titlecompound 57 which is crystallized from MeOH.

[0213] Physical data: mp 212-213° C. (dec.).

[0214] Anal. calcd for C₁₇H₂₀F₂N₂O₃S₂: C, 50.73; H, 5.01; N, 6.96.Found: C, 50.55; H, 5.08; N, 6.88.

Example 27 Preparation of2,2-difluoro-N-({(5S)-3-[3,5-difluoro-4-(1-oxidotetrahydro-2H-thiopyran-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide,Z-isomer (59).

[0215]

[0216] Condensation of 60 (prepared according to the procedure describedin U.S. Pat. No. 6,342,523) with 7 and triethylamine in DMF as describedin Example 3 for the preparation of 8 provides the title compound 59.

[0217] Physical data: mp 219-221° C.

[0218] HRMS calcd for C₁₇H₁₉F₄N₂O₃S₂ (M+H⁺) 439.0773, found 439.0772.

[0219] Anal. calcd for C₁₇H₁₈F₄N₂O₃S₂: C, 46.57; H, 4.14; N, 6.39.Found: C, 46.49; H, 4.18; N, 6.36.

Example 28 Preparation of2,2-difluoro-N-({(5S)-3-[4-(1-imino-1-oxidohexahydro-1λ⁴-thiopyran-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide,Z-isomer (61).

[0220]

[0221] Condensation of 62 (prepared according to the procedure describedin U.S. Pat. No. 6,342,523) with 7 and triethylamine in CH₂Cl₂ asdescribed in Example 3 for the preparation of 8 provides the titlecompound 61 which is purified by silica gel chromatography with 4%MeOH—CHCl₃ and crystallization from MeOH.

[0222] Physical data: mp 188-189° C.

[0223] MS (ESI+) m/z 418 (M+H⁺); MS (ESI−) m/z 416 (M−H).

[0224] Anal. calcd for C₁₇H₂₁F₂N₃O₃S₂: C, 48.91; H, 5.07; N, 10.06.Found: C, 48.73; H, 5.09; N, 9.93.

Example 29 Preparation of2,2-difluoro-N-({(5S)-3-[4-(1-imino-1-oxidohexahydro-1λ⁴-thiopyran-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide,E-isomer (63).

[0225]

[0226] Condensation of 64 (prepared according to the procedure describedin U.S. Pat. No. 6,342,523) with 7 and triethylamine in CH₂Cl₂ asdescribed in Example 3 for the preparation of 8 provides the titlecompound 63 which is purified by silica gel chromatography with 3.5%MeOH—CH₂Cl₂ and crystallization from MeOH.

[0227] Physical data: mp 184-185° C. (dec).

[0228] MS (ESI+) m/z 418 (M+H⁺), 440 (M+Na^(+).)

[0229] MS (ESI−) m/z 416 (M−H).

[0230] Anal. calcd for C₁₇H₂₁F₂N₃O₃S₂: C, 48.91; H, 5.07; N, 10.06.Found: C, 48.80; H, 5.09; N, 10.00.

EXAMPLE 30 Preparation of2,2-difluoro-N-({(5S)-3-[4-(1-methylimino-1-oxidohexahydro-1λ⁴-thiopyran-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide,Z-isomer (65).

[0231]

[0232] Following the procedure described in Example 4 for thepreparation of 11 the reaction of 66 (prepared according to theprocedure described in U.S. Pat. No. 6,342,523) with paraformaldehyde,TFA, and triethylsilane provides the title compound 65 which is purifiedby silica gel chromatography eluting first with 50% CH₃CN—CH₂Cl₂ andthen with 5% MeOH—CHCl₃.

[0233] Physical data: HRMS (FAB) calcd for C₁₈H₂₄F₂N₃O₃S₂ (M+H⁺)432.1227, found 432.1239.

[0234] Anal. calcd for C₁₈H₂₃F₂N₃O₃S₂: C, 50.10; H, 5.37; N, 9.74.Found: C, 50.15; H, 5.53; N, 9.48.

EXAMPLE 31 Preparation of2,2-difluoro-N-({(5S)-3-[4-(1-methylimino-1-oxidohexahydro-1λ⁴-thiopyran-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide,E-isomer (67).

[0235]

[0236] Following the procedure described in Example 4 for thepreparation of 11 the reaction of 68 (prepared according to theprocedure described in U.S. Pat. No. 6,342,523) with paraformaldehyde,TFA, and triethylsilane provides the title compound 83 which is purifiedby silica gel chromatography first with 50% CH₃CN-CH₂Cl₂ and a secondtime with 4% MeOH—CHCl₃.

[0237] Physical data: HRMS (FAB) calcd for C₁₈H₂₄F₂N₃O₃S₂ (M+H⁺)432.1227, found 432.1239.

[0238] Anal. calcd for C₁₈H₂₃F₂N₃O₃S₂: C, 50.10; H, 5.37; N, 9.74.Found: C, 50.09; H, 5.52; N, 9.43.

[0239] Pharmaceutical Salts

[0240] The compound of formula I may be used in its native form or as asalt. In cases where forming a stable nontoxic salt is desired,administration of the compound as a pharmaceutically acceptable salt maybe appropriate. Examples of pharmaceutically acceptable salts areorganic acid addition salts formed with acids which form a physiologicalacceptable anion, for example, tosylate, methanesulfonate, acetate,citrate, malonate, tartarate, succinate, benzoate, ascorbate,ketoglutarate, and glycerophosphate. Suitable inorganic salts may alsobe formed, including hydrochloride, hydrobromide, sulfate, nitrate,bicarbonate, and carbonate salts. Pharmaceutically acceptable salts maybe obtained using standard procedures well known in the art, for exampleby reacting a compound of the present invention with a suitable acidaffording a physiologically acceptable anion.

[0241] Doses for Individual/Combination Therapy

[0242] In combating the infective diseases caused by gram-positiveorganisms, the compound of the formula I can be used eitherindividually, or in combination with other antibiotics that are activeagainst gram-positive organisms. Some of the gram-positive antibioticsmay also have activity against gram-negative organisms.

[0243] Examples of such gram-positive antibiotics are listed in Table 1.TABLE 1 Gram-Positive Antibiotics That May Be Used In a CombinationTherapy With The Compound of Formula I AGENTS LO DOSE HI DOSE STD DOSEAMINOGLYCOSIDES Amikacin 15 mg/kg/day Gentamicin 1 mg/kg/day 5 mg/kg/day.5 mg/kg 2.5 mg/kg Spectinomycin 40 mg/kg Tobramycin 1 mg/kg/day 5mg/kg/day .5 mg/kg/day 5 mg/kg/day PENEMS Imipenem/cilastatin 62.5 mg 1g 6.25 mg/kg 25 mg/kg Meropenem 40 mg/kg .5 mg/kg 2.5 mg/kg 1^(ST) GENCEPHS Cefadroxil .25 g/day 2 g/day 30 mg/kg/day Cefazolin 62.5 mg 1.5 g6.25 mg/kg/day 100 mg/kg/day Cephalexin 62.5 mg 500 mg 6.25 mg/kg/day 50mg/kg/day 2^(ND) GEN CEPHS Cefaclor 62.5 mg 500 mg 5 mg/kg/day 40mg/kg/day Cefotetan 0.125 g 3 g 10 mg/kg/day 80 mg/kg/day Cefoxitin .25g 3 g 20 mg/kg/day 160 mg/kg/day Cefprozil 62.5 mg 500 mg 1.87mg/kg/dose 15 mg/kg/dose Cefuroxime 187.5 mg 3 g 31.25 mg 500 mg 12.5mg/kg/day 150 mg/kg/day 31.25 mg/kg/day 500 mg/kg/day Loracarbef 50 mg400 mg 3.75 mg/kg/day 500 mg/kg/day 3^(RD) GEN CEPHS Cefdinir 75 mg 600mg Cefixime 50 mg 400 mg Cefoperazone .5 g/day 12 g/day 25 mg/kg/day 150mg/kg/day Cefotaxime .25 g 2 g 12.5 mg/kg/dose 300 mg/kg/day Cefpodoxime25 mg 400 mg 10 mg/kg/day Ceftazidime 62.5 mg 2 g q8 25 mg/kg/day 150mg/kg/day Ceftibuten 2.25 mg/kg 400 mg 400 mg Ceftozoxime .25 g 4 g 12.5mg/kg/day 200 mg/kg/day Ceftriaxone 31.25 mg 2 g 12.5 mg/kg/day 100mg/kg/day 4^(TH) GEN CEPHS Cefepime 0.125 g 2 g 12.5 mg/kg 50 mg/kg q8MACROLIDES Azithromycin 62.5 mg 500 mg 62.5 mg 500 mg Clarithromycin62.5 mg 500 mg 7.5 mg/kg/day Dirithromycin 500 mg 1^(ST) GEN PENSPenicillin G 2 million units/day 30 million units/day 2000 units/kg/dy400,000 units/kg/day 2^(ND) GEN PENS Cloxacillin 62.5 mg 500 mg 12.5mg/kg/day 100 mg/kg/day Dicloxacillin 31.25 mg 500 mg 3.125 mg/kg/day100 mg/kg/day Nafcillin 125 mg 2 g 2.5 mg/kg 25 mg/kg Oxacillin 62.5 mg2 g 125 mg 1000 mg 25 mg/kg/day 200 mg/kg/day 12.5 mg/kg/day 100mg/kg/day 3^(RD) GEN PENS Amoxicillin 62.5 mg 875 mg 5 mg/kg/day 45mg/kg Amoxicillin/clavulanic acid 62.5 mg 875 mg 6.25 mg/kg/day 45mg/kg/day Ampicillin 62.5 mg 12 g/day q4 6.25 mg/kg/day 300 mg/kg/dayAmpicillin/sulbactam 0.375 g 3 g 300 mg/kg/day 4^(TH) GEN PENSMezlocillin 0.375 g 4 g 75 mg/kg Piperacillin 1.5 g/day 24 g day 25mg/kg/day 300 mg/kg/day Piperacillin/tazobactam 240 mg/kg/dayTicarcillin .25 g 4 g 12.5 mg/kg/day 300 mg/kg/dayTicarcillin/clavulanate 50 mg/kg/day 300 mg/kg/day 0.775 g 3.1 g 1^(ST)GEN QUINOLONES Nalidixic Acid 55 mg/kg/day 2^(ND) GEN QUINOLONESCiprofloxacin 50 mg 750 mg 2.5 mg/kg/dose 15 mg/kg/dose 62.5 mg 750 mg2.5 mg/kg/dose 15 mg/kg/dose Enoxacin 50 mg 400 mg Lomefloxacin 400 mgNorfloxacin 400 mg Ofloxacin 50 mg 400 mg 3^(RD) GEN QUINOLONESLevofloxacin 62.5 mg 750 mg Sparfloxacin 50 mg 400 mg 4^(TH) GENQUINOLONES Alatrofloxacin 50 mg 300 mg Gatifloxacin 50 mg 400 mgMoxifloxacin 400 mg SULFAS Trimethoprim/sulfamethoxazole 15 mg 800 mg3.75 mg/day 150 mg/day Sulfisoxazole 18.75 mg 150 mg Sulfamethoxazole.25 g 2 g TETRACYCLINES Doxycycline 5 mg 100 mg Minocycline 25 mg 200 mgTetracycline 62.5 mg 500 mg OTHER Chloramphenicol 12.5 mg/kg/day 100mg/kg/day Clindamycin 150 mg 900 mg 37.5 mg 450 mg 5 mg/kg/day 40mg/kg/day 2 mg/kg/day 25 mg/kg/day Quinupristin/dalfopristin 1.875 mg/kg7.5 mg/kg q8 Fosfomycin 3 g Nitrofurantoin 12.5 mg 100 mg 1.25 mg/kg/day7 mg/kg/day Rifampin 2.5 mg/kg 600 mg/kg 2.5 mg/kg 600 mg/kgTrimethoprim 25 mg 200 mg 10 mg/kg/day Vancomycin 1 g 2.5 mg/kg q6 15mg/kg q8

[0244] In combating the infective diseases caused by gram-positive andgram-negative organisms, the compound of the formula I can be used incombination with other antibiotics that are active against gram-negativeorganisms. Examples of such gram-negative antibiotics are listed inTable 2. Some of gram-negative antibiotics may also have activityagainst gram-positive organisms. TABLE 2 Gram-Negative Antibiotics ThatMay Be Used In a Combination Therapy with The Compound of Formula IAGENTS LO DOSE HI DOSE STD DOSE AMINO- GLYCOSIDES Amikacin 15 mg/kg/dayGentamicin 0.75 mg/kg/day 5 mg/kg/day 0.5 mg/kg 2.5 mg/kg Spectinomycin40 mg/kg Tobramycin 0.75 mg/kg/day 5 mg/kg/day 0.5 mg/kg/day 5 mg/kg/dayPENEMS Imipenem/cilastatin 62.5 mg 1 g 6.25 mg/kg 25 mg/kg Meropenem 40mg/kg 0.5 mg/kg 2.5 mg/kg 2^(ND) GEN CEPHS Cefaclor 62.5 mg 500 mg 5mg/kg/day 40 mg/kg/day Cefotetan 0.125 g 3 g 10 mg/kg/day 80 mg/kg/dayCefoxitin 0.25 g 3 g 20 mg/kg/day 160 mg/kg/day Cefprozil 62.5 mg 500 mg1.875 mg/kg/dose 15 mg/kg/dose Cefuroxime 187.5 mg 3 g 31.25 mg 500 mg12.5 mg/kg/day 150 mg/kg/day 31.25 mg/kg/day 500 mg/kg/day Loracarbef 50mg 400 mg 3.75 mg/kg/day 500 mg/kg/day 3^(RD) GEN CEPHS Cefdinir 75 mg600 mg qd Cefixime 50 mg 400 mg Cefoperazone 0.25 g/day 12 g/day 25mg/kg/day 150 mg/kg/day Cefotaxime 0.25 g 2 g 12.5 mg/kg/dose 300mg/kg/day Cefpodoxime 25 mg 400 mg 10 mg/kg/day Ceftazidime 62.5 mg 2 gq8 25 mg/kg/day 150 mg/kg/day Ceftibuten 2.25 mg/kg 400 mg 400 mgCeftozoxime 0.25 g 4 g 12.5 mg/kg/day 200 mg/kg/day Ceftriaxone 31.25 mg2 g 12.5 mg/kg/day 100 mg/kg/day 4^(TH) GEN CEPHS Cefepime 0.125 g 2 g12.5 mg/kg 50 mg/kg q8 MACROLIDES Azithromycin 62.5 mg 500 mg 62.5 mg500 mg Clarithromycin 62.5 mg 500 mg 7.5 mg/kg/day Dirithromycin 500 mg3^(RD) GEN PENS Amoxicillin 62.5 mg 875 mg 5 mg/kg/day 45 mg/kgAmoxicillin/ 62.5 mg 875 mg clavulanic 6.25 mg/kg/day 45 mg/kg/day acidAmpicillin 62.5 mg 12 g/day q4 6.25 mg/kg/day 300 mg/kg/day Ampicillin/0.375 g 3 g 300 mg/kg/day sulbactam 4^(TH) GEN PENS Mezlocillin 0.375 g4 g 75 mg/kg Piperacillin 1.5 g/day 24 g day 25 mg/kg/day 300 mg/kg/dayPiperacillin/ 240 mg/kg/day tazobactam Ticarcillin 0.25 g 4 g 12.5mg/kg/day 300 mg/kg/day Ticarcillin/ 50 mg/kg/day 300 mg/kg/dayclavulanate 0.775 g 3.1 g 1^(ST) GEN QUINOLONES Nalidixic Acid 55mg/kg/day 2^(ND) GEN QUINOLONES Ciprofloxacin 50 mg 750 mg 2.5mg/kg/dose 15 mg/kg/dose 62.5 mg 750 mg 2.5 mg/kg/dose 15 mg/kg/doseEnoxacin 50 mg 400 mg Lomefloxacin 400 mg Norfloxacin 400 mg Ofloxacin50 mg 400 mg 3^(RD) GEN QUINOLONES Levofloxacin 62.5 mg 750 mgSparfloxacin 50 mg 400 mg 4^(TH) GEN QUINOLONES Alatrofloxacin 50 mg 300mg Gatifloxacin 50 mg 400 mg Moxifloxacin 400 mg SULFAS Trimethoprim/15/200 mg sulfamethox azole 3.75 mg/day 150 mg/day Sulfisoxazole 18.75mg 150 mg Sulfamethoxazole 0.25 g 2 g TETRACYCLINES Doxycycline 5 mg 100mg Minocycline 25 mg 200 mg Tetracycline 62.5 mg 500 mg OTHERChloramphenicol 12.5 mg/kg/day 100 mg/kg/day Aztreonam 125 mg 2 g 37.5mg 450 mg 5 mg/kg/day 40 mg/kg/day 2 mg/kg/day 25 mg/kg/day Fosfomycin 3g Nitrofurantoin 12.5 mg 100 mg 1.25 mg/kg/day 7 mg/kg/day 2.5 mg/kg 600mg/kg Trimethoprim 25 mg 200 mg 10 mg/kg/day

[0245] In Tables 1 and 2, the term “Lo Dose” means the recommended lowerdosage for the combination therapy of the invention. It may be adjustedeven lower depending on the requirements of each subject being treatedand the severity of the bacterial infection. The lowest dosage possiblemay be 0.1 mg when combined with the compound of formula I of thepresent invention. The term “Hi Dose” means the recommended highestdosage in the combination therapy. It may be changed hereafter accordingto the US FDA standard. The term “Std Dose” means the recommendedstandard dosage for the combination therapy of the present invention. Itmay be adjusted even lower depending on the requirements of each subjectbeing treated and the severity of the bacterial infection. A specificantibiotic may have more than one the recommended dosage ranges.

[0246] Generally, an antibacterially effective amount of dosage of thecompound of formula I of the present invention, either administeredindividually or in combination with other antibiotics, will be in therange of about 0.1 to about 400 mg/kg of body weight/day, morepreferably about 1.0 to about 50 mg/kg of body weight/day. It is to beunderstood that the dosages of active component(s) may vary dependingupon the requirements of each subject being treated and the severity ofthe bacterial infection. In average, the effective amount of an activecomponent is about 20 mg to 800 mg and preferable is about 200 mg to 600mg per day.

[0247] The desired dose may conveniently be presented in a single doseor as divided into multiple doses administered at appropriate intervals,for example, as two, three, four or more sub-doses per day. The sub-doseitself may be further divided, e.g., into a number of discrete looselyspaced administrations; such as multiple inhalations from an insufflatoror by application of a plurality of drops into the eye.

[0248] Also, it is to be understood that the initial dosage administeredmay be increased beyond the above upper level in order to rapidlyachieve the desired plasma concentration. On the other hand, the initialdosage may be smaller than the optimum and the daily dosage may beprogressively increased during the course of treatment depending on theparticular situation.

[0249] In cases of local administration or selective uptake, theeffective local concentration of the drug may not be related to plasmaconcentration and other procedures know in the art may be used todetermine the desired dosage amount.

[0250] For the combination therapy, the compound of formula I may beadministered concurrently or concomitantly with other antibiotics. Theterm “concurrently” means the subject being treated takes one drugwithin about 5 minutes of taking the other drug. The term“concomitantly” means the subject being treated takes one drug withinthe same treatment period of taking the other drug. The same treatmentperiod is preferably within twelve hours and up to forty-eight hours.

[0251] For the combination therapy, the compound of formula I, and oneor more other antibiotics may be administered in the same physical formor separately, i.e., they may be administered in the same deliveryvehicle or in different delivery vehicles.

[0252] For the combination therapy, some of the antibiotics may furtherbe used with a β-Lactamase inhibitor. For example, Imipenem may be usedwith cilastatin, Ampicillin may be used with sulbactam, Piperacillin maybe used with tazobactam, and Ampicillin may be used with sulbactam.

[0253] Specifically, the combination therapy of the present invention isthe compound of formula I of the present invention with Amikacin.

[0254] Specifically, the combination therapy of the present invention isthe compound of formula I of the present invention with Gentamicin.

[0255] Specifically, the combination therapy of the present invention isthe compound of formula I of the present invention with Spectinomycin.

[0256] Specifically, the combination therapy of the present invention isthe compound of formula I of the present invention with Tobramycin.

[0257] Specifically, the combination therapy of the present invention isthe compound of formula I of the present invention withImipenem/cilastatin.

[0258] Specifically, the combination therapy of the present invention isthe compound of formula I of the present invention with Meropenem.

[0259] Specifically, the combination therapy of the present invention isthe compound of formula I of the present invention with Cefadroxil.

[0260] Specifically, the combination therapy of the present invention isthe compound of formula I of the present invention with Cefazolin.

[0261] Specifically, the combination therapy of the present invention isthe compound of formula I of the present invention with Cephalexin.

[0262] Specifically, the combination therapy of the present invention isthe compound of formula I of the present invention with Cefaclor.

[0263] Specifically, the combination therapy of the present invention isthe compound of formula I of the present invention with Cefotetan.

[0264] Specifically, the combination therapy of the present invention isthe compound of formula I of the present invention with Cefoxitin.

[0265] Specifically, the combination therapy of the present invention isthe compound of formula I of the present invention with Cefprozil.

[0266] Specifically, the combination therapy of the present invention isthe compound of formula I of the present invention with Cefuroxime.

[0267] Specifically, the combination therapy of the present invention isthe compound of formula I of the present invention with Loracarbef.

[0268] Specifically, the combination therapy of the present invention isthe compound of formula I of the present invention with Cefdinir.

[0269] Specifically, the combination therapy of the present invention isthe compound of formula I of the present invention with Cefixime.

[0270] Specifically, the combination therapy of the present invention isthe compound of formula I of the present invention with Cefoperazone.

[0271] Specifically, the combination therapy of the present invention isthe compound of formula I of the present invention with Cefotaxime.

[0272] Specifically, the combination therapy of the present invention isthe compound of formula I of the present invention with Cefpodoxime.

[0273] Specifically, the combination therapy of the present invention isthe compound of formula I of the present invention with Ceftazidime.

[0274] Specifically, the combination therapy of the present invention isthe compound of formula I of the present invention with Ceftibuten.

[0275] Specifically, the combination therapy of the present invention isthe compound of formula I of the present invention with Ceftozoxime.

[0276] Specifically, the combination therapy of the present invention isthe compound of formula I of the present invention with Ceftriaxone.

[0277] Specifically, the combination therapy of the present invention isthe compound of formula I of the present invention with Cefepime.

[0278] Specifically, the combination therapy of the present invention isthe compound of formula I of the present invention with Azithromycin.

[0279] Specifically, the combination therapy of the present invention isthe compound of formula I of the present invention with Clarithromycin.

[0280] Specifically, the combination therapy of the present invention isthe compound of formula I of the present invention with Dirithromycin.

[0281] Specifically, the combination therapy of the present invention isthe compound of formula I of the present invention with Penicillin G.

[0282] Specifically, the combination therapy of the present invention isthe compound of formula I of the present invention with Cloxacillin.

[0283] Specifically, the combination therapy of the present invention isthe compound of formula I of the present invention with Dicloxacillin.

[0284] Specifically, the combination therapy of the present invention isthe compound of formula I of the present invention with Nafcillin.

[0285] Specifically, the combination therapy of the present invention isthe compound of formula I of the present invention with Oxacillin.

[0286] Specifically, the combination therapy of the present invention isthe compound of formula I of the present invention with Amoxicillin.

[0287] Specifically, the combination therapy of the present invention isthe compound of formula I of the present invention withAmoxicillin/clavulanic acid.

[0288] Specifically, the combination therapy of the present invention isthe compound of formula I of the present invention with Ampicillin.

[0289] Specifically, the combination therapy of the present invention isthe compound of formula I of the present invention withAmpicillin/sulbactam.

[0290] Specifically, the combination therapy of the present invention isthe compound of formula I of the present invention with Mezlocillin.

[0291] Specifically, the combination therapy of the present invention isthe compound of formula I of the present invention with Piperacillin.

[0292] Specifically, the combination therapy of the present invention isthe compound of formula I of the present invention withPiperacillin/tazobactam.

[0293] Specifically, the combination therapy of the present invention isthe compound of formula I of the present invention with Ticarcillin.

[0294] Specifically, the combination therapy of the present invention isthe compound of formula I of the present invention withTicarcillin/clavulanate.

[0295] Specifically, the combination therapy of the present invention isthe compound of formula I of the present invention with Nalidixic Acid.

[0296] Specifically, the combination therapy of the present invention isthe compound of formula I of the present invention with Ciprofloxacin.

[0297] Specifically, the combination therapy of the present invention isthe compound of formula I of the present invention with Enoxacin.

[0298] Specifically, the combination therapy of the present invention isthe compound of formula I of the present invention with Lomefloxacin.

[0299] Specifically, the combination therapy of the present invention isthe compound of formula I of the present invention with Norfloxacin.

[0300] Specifically, the combination therapy of the present invention isthe compound of formula I of the present invention with Ofloxacin.

[0301] Specifically, the combination therapy of the present invention isthe compound of formula I of the present invention with Levofloxacin.

[0302] Specifically, the combination therapy of the present invention isthe compound of formula I of the present invention with Sparfloxacin.

[0303] Specifically, the combination therapy of the present invention isthe compound of formula I of the present invention with Alatrofloxacin.

[0304] Specifically, the combination therapy of the present invention isthe compound of formula I of the present invention with Gatifloxacin.

[0305] Specifically, the combination therapy of the present invention isthe compound of formula I of the present invention with Moxifloxacin.

[0306] Specifically, the combination therapy of the present invention isthe compound of formula I of the present invention withTrimethoprim/sulfamethoxazole.

[0307] Specifically, the combination therapy of the present invention isthe compound of formula I of the present invention with Sulfisoxazole.

[0308] Specifically, the combination therapy of the present invention isthe compound of formula I of the present invention withSulfamethoxazole.

[0309] Specifically, the combination therapy of the present invention isthe compound of formula I of the present invention with Doxycycline.

[0310] Specifically, the combination therapy of the present invention isthe compound of formula I of the present invention with Minocycline.

[0311] Specifically, the combination therapy of the present invention isthe compound of formula I of the present invention with Tetracycline.

[0312] Specifically, the combination therapy of the present invention isthe compound of formula I of the present invention with Aztreonam.

[0313] Specifically, the combination therapy of the present invention isthe compound of formula I of the present invention with Chloramphenicol.

[0314] Specifically, the combination therapy of the present invention isthe compound of formula I of the present invention with Clindamycin.

[0315] Specifically, the combination therapy of the present invention isthe compound of formula I of the present invention withQuinupristin/dalfopristin.

[0316] Specifically, the combination therapy of the present invention isthe compound of formula I of the present invention with Fosfomycin.

[0317] Specifically, the combination therapy of the present invention isthe compound of formula I of the present invention with Metronidazole.

[0318] Specifically, the combination therapy of the present invention isthe compound of formula I of the present invention with Nitrofurantoin.

[0319] Specifically, the combination therapy of the present invention isthe compound of formula I of the present invention with Rifampin.

[0320] Specifically, the combination therapy of the present invention isthe compound of formula I of the present invention with Trimethoprim.

[0321] Specifically, the combination therapy of the present invention isthe compound of formula I of the present invention with Vancomycin.

[0322] Routes of Administration

[0323] In therapeutic use for treating, or combating, bacterialinfections in a mammal (i.e. human and animals) a compound of thepresent invention, its pharmaceutical compositions, or combining withother antibacterial agents can be administered orally, parenterally,topically, rectally, transmucosally, or intestinally.

[0324] Parenteral administrations include indirect injections togenerate a systemic effect or direct injections to the afflicted area.Examples of parenteral administrations are subcutaneous, intravenous,intramuscular, intradermal, intrathecal, intraocular, intranasal,intravetricular injections or infusions techniques.

[0325] Topical administrations include the treatment of infectious areasor organs readily accessibly by local application, such as, for example,eyes, ears including external and middle ear infections, vaginal, openwound, skins including the surface skin and the underneath dermalstructures, or other lower intestinal tract. Topical administrationsalso include transdermal delivery to generate a systemic effect.

[0326] The rectal administration includes the form of suppositories.

[0327] The transmucosal administration includes nasal aerosol orinhalation applications.

[0328] The preferred routes of administration are oral and parenteral.

[0329] Composition/Formulation

[0330] Pharmaceutical compositions of the present invention may bemanufactured by processes well known in the art, e.g., by means ofconventional mixing, dissolving, granulation, dragee-making, levigating,emulsifying, encapsulating, entrapping, lyophilizing processes or spraydrying.

[0331] Pharmaceutical compositions for use in accordance with thepresent invention may be formulated in conventional manner using one ormore physiologically acceptable carriers comprising excipients andauxiliaries which facilitate processing of the active compounds intopreparations which can be used pharmaceutically. Proper formulation isdependent upon the route of administration chosen.

[0332] For oral administration, the compounds can be formulated bycombining the active compounds with pharmaceutically acceptable carrierswell known in the art.

[0333] Such carriers enable the compounds of the invention to beformulated as tablets, pills, lozenges, dragees, capsules, liquids,solutions, emulsions, gels, syrups, slurries, suspensions and the like,for oral ingestion by a patient. A carrier can be at least one substancewhich may also function as a diluent, flavoring agent, solubilizer,lubricant, suspending agent, binder, tablet disintegrating agent, andencapsulating agent. Examples of such carriers or excipients include,but are not limited to, magnesium carbonate, magnesium stearate, talc,sugar, lactose, sucrose, pectin, dextrin, mnnitol, sorbitol, starches,gelatin, cellulosic materials, low melting wax, cocoa butter or powder,polymers such as polyethylene glycols and other pharmaceuticalacceptable materials.

[0334] Dragee cores are provided with suitable coatings. For thispurpose, concentrated sugar solutions may be used which may optionallycontain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel,polyethylene glycol, and/or titanium dioxide, lacquer solutions, andsuitable organic solvents or solvent mixtures. Dyestuffs or pigments maybe added to the tablets or dragee coatings for identificatin or tocharacterize different combinations of active compound doses.

[0335] Pharmaceutical compositions which can be used orally includepush-fit capsules made of gelatin, as well as soft, sealed capsules madeof gelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules can contain the active ingredients in admixture with a fillersuch as lactose, a binder such as starch, and/or a lubricant such astalc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compounds may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, liquid polyethyleneglycols, cremophor, capmul, medium or long chain mono-, fi- ortriglycerides. Stabilizers may be added in these formulations, also.

[0336] Liquid form compositions include solutions, suspensions andemulsions. For example, there may be provided solutions of the compoundsof this invention dissolved in water and water-propylene glycol andwater-polyethylene glycol systems, optionally containing suitableconventional coloring agents, flavoring agents, stabilizers andthickening agents.

[0337] The compounds may also be formulated for parenteraladministration, e.g., by injections, bolus injection or continuousinfusion. Formulations for parenteral administration may be presented inunit dosage form, e.g., in ampoules or in multi-dose containers, with anadded preservative. The compositions may take such forms as suspensions,solutions or emulsions in oily or aqueous vehicles, and may containformulating materials such as suspending, stabilizing and/or dispersingagents.

[0338] For injection, the compounds of the invention may be formulatedin aqueous solution, preferably in physiologically compatible buffers orphysiological saline buffer. Suitable buffering agents include trisodiumorthophosphate, sodium bicarbonate, sodium citrate, N-methylglucamine,L(+)-lysine and L(+)-arginine.

[0339] Parenteral administrations also include aqueous solutions of awater soluble form, such as, without limitation, a salt, of the activecompound. Additionally, suspensions of the active compounds may beprepared in a lipophilic vehicle. Suitable lipophilic vehicles includefatty oils such as sesame oil, synthetic fatty acid esters such as ethyloleate and triglycerides, or materials such as liposomes. Aqueousinjection suspensions may contain substances which increase theviscosity of the suspension, such as sodium carboxymethyl cellulose,sorbitol, or dextran. Optionally, the suspension may also containsuitable stabilizers and/or agents that increase the solubility of thecompounds to allow for the preparation of highly concentrated solutions.

[0340] Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g., sterile, pyrogen-free water,before use.

[0341] For suppository administration, the compounds may also beformulated by mixing the agent with a suitable non-irritating excipientwhich is solid at room temperature but liquid at rectal temperature andtherefore will melt in the rectum to release the drug. Such materialsinclude cocoa butter, beeswax and other glycerides.

[0342] For administration by inhalation, compounds of the presentinvention can be conveniently delivered through an aerosol spray in theform of solution, dry powder, or suspensions. The aerosol may use apressurized pack or a nebulizer and a suitable propellant. In the caseof a pressurized aerosol, the dosage unit may be controlled by providinga valve to deliver a metered amount. Capsules and cartridges of, forexample, gelatin for use in an inhaler may be formulated containing apower base such as lactose or starch.

[0343] For topical applications, the pharmaceutical composition may beformulated in a suitable ointment containing the active componentsuspended or dissolved in one or more carriers. Carriers for topicaladministration of the compounds of this invention include, but are notlimited to, mineral oil, liquid petrolatum, white petrolatum, propyleneglycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax andwater. Aternatively, the pharmaceutical compositions can be formulatedin a suitable lotion such as suspensions, emulsion, or cream containingthe active components suspended or dissolved in one or morepharmaceutically acceptable carriers. Suitable carriers include, but arenot limited to, mineral oil, sorbitan monostearate, polysorbate 60,cetyl esters wax, ceteary alcohol, 2-octyldodecanol, benzyl alcohol andwater.

[0344] For ophthalmic and otitis uses, the pharmaceutical compositionsmay be formulated as micronized suspensions in isotonic, pH adjustedsterile saline, or preferably, as solutions in isotonic, pH adjustedsterile saline, either with or without a preservative such asbenzylalkonium chloride. Alternatively, for ophthalmic uses, thepharmaceutical compositions may be formulated in an ointment such aspetrolatum.

[0345] In addition to the formulations described previously, thecompounds may also be formulated as depot preparations. Such long actingformulations may be in the forms of implants. A compound of thisinvention may be formulated for this route of administration withsuitable biopolymers, hydrophbic materials, or as a sparing solublederivative such as, without limitation, a sparingly soluble salt.

[0346] Additionally, the compounds may be delivered using asustained-release system. Various sustained-release materials have beenestablished and are well known by those skilled in the art.Sustained-release capsules may, depending on their chemical nature,release the compounds for 24 hours up to several days. Depending on thechemical natrue and the biological stability of the therapeutic reagent,additional strategies for protein stabilization may be employed.

[0347] The quantity of active component, that is the compound thisinvention, in the pharmaceutical composition and unit dosage formthereof may be varied or adjusted widely depending upon the manner ofadministration, the potency of the particular compound and the desiredconcentration. Determination of a therapeutically effective amount iswell within the capability of those skilled in the art. Generally, thequantity of active component will range between 0.5% to 90% by weight ofthe composition.

We claim:
 1. A compound of formula I

or pharmaceutically acceptable salt wherein R is —CH₂— or —CH₂CH₂—; R²and R³ are independently —H or —F; X is —N— or —CH—; Y is —SO—, —SO₂—,or —SONR⁴—; and R⁴ is —H or —C₁₋₄alkyl.
 2. A compound of claim 1 whereinR² and R³ are H.
 3. A compound of claim 1 wherein R² and R³ are F.
 4. Acompound of claim 1 wherein one of the R² and R³ is H, the other one isF.
 5. A compound of claim 1 wherein R is —CH₂—.
 6. A compound of claim 1wherein X is N.
 7. A compound of claim 1 wherein X is CH.
 8. A compoundof claim 1 wherein Y is SO₂.
 9. A compound of claim 1 wherein Y is SO.10. A compound of claim 1 wherein Y is S(═O)NR⁴.
 11. A compound of claim10 wherein R⁴ is H or CH₃.
 12. A compound of claim 1 which is a compoundof formula Ia, Ib, Ic, or Id.


13. A compound of claim 1 which is (1)2,2-difluoro-N-[((5S)-3-{3-fluoro-4-[1-(methylimino)-1-oxido-1λ⁴,4-thiazinan-4-yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]ethanethioamide,(2)2,2-difluoro-N-({(5S—)-3-[3-fluoro-4-(1-imino-1-oxidohexahydro-1λ⁴-thiopyran-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide(Z-isomer), (3)2,2-difluoro-N-({(5S)-3-[3-fluoro-4-(1-imino-1-oxidohexahydro-1λ⁴-thiopyran-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide(E-isomer), (4)2,2-difluoro-N-({(5S)-3-[3-fluoro-4-(1-methylimino-1-oxidohexahydro-1λ⁴-thiopyran-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide(Z-isomer), (5)2,2-difluoro-N-({(55)-3-[3-fluoro-4-(1-methylimino-1-oxidohexahydro-1λ⁴-thiopyran-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide(E-isomer), (6)2,2-difluoro-N-({(5S)-3-[4-(1,1-dioxidothiomorpholin-4-yl)-3-fluorophenyl]2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide, (7)2,2-difluoro-N-({(5S-3-[4-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-3fluorophenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide,(8)2,2-difluoro-N-({(5S)-3-[3-fluoro-4-(1-oxidotetrahydro-2H-thiopyran-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide(Z-Isomer), (9)2,2-difluoro-N-({(5S)-3-[3-fluoro-4-(1-oxidothiomorpholin-5-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide,(10)2,2-difluoro-N-({(5S)-3-[4-(1,1-dioxido-1,4-thiazepan-4-yl)-3-fluorophenyl]2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide, (11)2,2-difluoro-N-({(5S)-3-[4-(1,1-dioxido-1,4-thiazepan-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide,(12)2,2-difluoro-N-({(5S)-3-[4-(1,1-dioxidothiomorpholin-4-yl)-3,5-difluorophenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide,(13)2,2-difluoro-N-({(5S)-3-[4-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide,(14)2,2-difluoro-N-({(5S)-3-[3,5-difluoro-4-(1-oxidothiomorpholin-4-yl)phenyl]2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide,(15)2,2-difluoro-N-({(5S)-3-[4-(1,1-dioxido-1,4-thiazepan-4-yl)-3,5-difluorophenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide,(16)2,2-difluoro-N-({(5S)-3-[4-(1,1-dioxidothiomorpholin-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide,(17)2,2-difluoro-N-({(5S)-3-[4-(1-oxidothiomorpholin-4-yl)phenyl]-2-oxo-1,3oxazolidin-5-yl}methyl)ethanethioamide, (18)2,2-difluoro-N-({(5S)-3-[3-fluoro-4-(1-imino-1-oxido-1λ⁴,4-thiazinan-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide,(19)2,2-difluoro-N-({(5S)-3-[3-fluoro-4-(1-oxido-1,4-thiazepan-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide,(20) 2,2-difluoro-N-({(5S)-3-[4-(1-imino-1-oxido-1λ⁴,4-thiazinan-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide,(21) 2,2-difluoro-N-(((5S)-3-{4-[1-(methylimino)-1-oxido-1λ⁴,4-thiazinan-4-yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]ethanethioamide,(22)2,2-difluoro-N-({(5S)-3-[3-fluoro-4-(1-oxidotetrahydro-2H-thiopyran-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide(E-Isomer), (23)2,2-difluoro-N-({(5S)-3-[4-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)phenyl]2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide,(24)2,2-difluoro-N-({(5S)-3-[4-(1-oxidotetrahydro-2H-thiopyran-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide(Z-isomer), (25)2,2-difluoro-N-({(5S)-3-[3,5-difluoro-4-(1-oxidotetrahydro-2H-thiopyran-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide(E-isomer), (26)2,2-difluoro-N-({(5S)-3-[4-(1-oxidotetrahydro-2H-thiopyran-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide(E-isomer), (27)2,2-difluoro-N-({(5S)-3-[3,5-difluoro-4-(1-oxidotetrahydro-2H-thiopyran-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide(Z-isomer), (28)2,2-difluoro-N-({(5S)-3-[4-(1-imino-1-oxidohexahydro-1λ⁴-thiopyran-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide(Z-isomer), (29)2,2-difluoro-N-({(5S)-3-[4-(1-imino-1-oxidohexahydro-1λ⁴-thiopyran-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide(E-isomer), (30)2,2-difluoro-N-({(5S)-3-[4-(1-methylimino-1-oxidohexahydro-1λ⁴-thiopyran-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide(Z-isomer), or (31)2,2-difluoro-N-({(5S)-3-[4-(1-methylimino-1-oxidohexahydro-1-λ⁴,4-thiopyran-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide(E-isomer).
 14. A method for treating bacteria infections comprisingadministering to a mammal being treated a pharmaceutically effectiveamount of the compound of claim
 1. 15. The method of claim 14 whereinthe compound of claim 1 is administered parenterally, topically,rectally, or intranasally.
 16. The method of claim 14 wherein thecompound of claim 1 is administered orally.
 17. The method of claim 15wherein parenteral administration is subcutaneous, intravenous,intramuscular, intradermal, intrathecal, intraocular, intravetricularinjection.
 18. The method of claim 15 wherein said compound isadministered in an amount of from about 0.1 to about 100 mg/kg of bodyweight/day.
 19. The method of claim 15 wherein said compound isadministered in an amount of from about 1 to about 50 mg/kg of bodyweight/day.
 20. The method of claim 14 wherein said infection is skininfection.
 21. The method of claim 14 wherein the infection is eyeinfection.
 22. The method of claim 14 wherein the infection is earinfection.
 23. The method of claim 14 wherein said mammal is human. 24.The method of claim 14 wherein said mammal is an animal.
 25. Apharmaceutical composition comprising the compound of claim 1 or itspharmaceutically acceptable salts thereof and a pharmaceuticallyacceptable carrier.
 26. A method for treating bacteria infections in amammal comprising administering to said mammal (a) a pharmaceuticallyeffective amount of the compound of claim 1 or a pharmaceuticallyeffective salt thereof; and (b) a pharmaceutically effective amount ofat least one antibiotic or a pharmaceutically effective salt thereof.27. The method of claim 26 wherein the antibiotic is Amikacin,Gentamicin, Spectinomycin, Tobramycin, Imipenem, Meropenem, Cefadroxil,Cefazolin, Cephalexin, Cefaclor, Cefotetan, Cefoxitin, Cefprozil,Cefuroxime, Loracarbef, Cefdinir, Cefixime, Cefoperazone, Cefotaxime,Cefpodoxime, Ceftazidime, Ceftibuten, Ceftozoxime, Ceftriaxone,Cefepime, Azithromycin, Clarithromycin, Dirithromycin, Penicillin G,Cloxacillin, Dicloxacillin, Nafcillin, Oxacillin, Amoxicillin,Ampicillin, Mezlocillin, Piperacillin, Nalidixic Acid, Ciprofloxacin,Enoxacin, Lomefloxacin, Norfloxacin, Ofloxacin, Levofloxacin,Sparfloxacin, Alatrofloxacin, Gatifloxacin, Moxifloxacin, Trimethoprim,Sulfisoxazole, Sulfamethoxazole, Doxycycline, Minocycline, Tetracycline,Aztreonam, Chloramphenicol, Clindamycin, Quinupristin, Fosfomycin,Metronidazole, Nitrofurantoin, Rifampin, Trimethoprim, or Vancomycin.28. A method for treating bacteria infections caused by gram-positivebacteria in a mammal comprising administering to said mammal (a) apharmaceutically effective amount of compound of the formula I as shownin claim 1 or a pharmaceutically effective salt thereof; and (b) apharmaceutically effective amount of at least one antibiotic or apharmaceutically effective salt thereof.
 29. The method of claim 28wherein the antibiotic is Amikacin, Gentamicin, Spectinomycin,Tobramycin, Imipenem, Meropenem, Cefadroxil, Cefazolin, Cephalexin,Cefaclor, Cefotetan, Cefoxitin, Cefprozil, Cefuroxime, Loracarbef,Cefdinir, Cefixime, Cefoperazone, Cefotaxime, Cefpodoxime, Ceftazidime,Ceftibuten, Ceftozoxime, Ceftriaxone, Cefepime, Azithromycin,Clarithromycin, Dirithromycin, Penicillin G, Cloxacillin, Dicloxacillin,Nafcillin, Oxacillin, Amoxicillin, Ampicillin, Mezlocillin,Piperacillin, Nalidixic Acid, Ciprofloxacin, Enoxacin, Lomefloxacin,Norfloxacin, Ofloxacin, Levofloxacin, Sparfloxacin, Alatrofloxacin,Gatifloxacin, Moxifloxacin, Trimethoprim, Sulfisoxazole,Sulfamethoxazole, Doxycycline, Minocycline, Tetracycline,Chloramphenicol, Clindamycin, Quinupristin/dalfopristin, Fosfomycin,Nitrofurantoin, Rifampin, Trimethoprim, or Vancomycin.
 30. A method fortreating bacteria infections caused by gram-negative bacteria in amammal comprising administering to said mammal (a) a pharmaceuticallyeffective amount of the compound of claim 1 or a pharmaceuticallyeffective salt thereof, and (b) a pharmaceutically effective amount ofone or more antibiotics or a pharmaceutically effective salt thereof.31. The method of claim 30 wherein the antibiotic is Amikacin,Gentamicin, Spectinomycin, Tobramycin, Imipenem, Meropenem, Cefaclor,Cefotetan, Cefoxitin, Cefprozil, Cefuroxime, Loracarbef, Cefdinir,Cefixime, Cefoperazone, Cefotaxime, Cefpodoxime, Ceftazidime,Ceftibuten, Ceftozoxime, Ceftriaxone, Cefepime, Azithromycin,Clarithromycin, Dirithromycin, Amoxicillin, Amoxicillin, Ampicillin,Ampicillin, Mezlocillin, Piperacillin, Piperacillin, Nalidixic Acid,Ciprofloxacin, Enoxacin, Lomefloxacin, Norfloxacin, Ofloxacin,Levofloxacin, Sparfloxacin, Alatrofloxacin, Gatifloxacin, Moxifloxacin,Trimethoprim, Sulfisoxazole, Sulfamethoxazole, Doxycycline, Minocycline,Tetracycline, Aztreonam, Chloramphenicol, Fosfomycin, Nitrofurantoin, orTrimethoprim.
 32. The method of claims 26 wherein the compound offormula I and the other antibiotic are administered parenterally,topically, rectally, or intranasally.
 33. The method of claims 26wherein the compound of formula I and the other antibiotic areadministered orally.
 34. The method of claim 32 wherein parenteraladministration is subcutaneous, intravenous, intramuscular, intradermal,intrathecal, intraocular, intravetricular injection.
 35. The method ofclaims 26 wherein said infection is skin infection.
 36. The method ofclaims 26 wherein said mammal is human.
 37. The method of claims 26wherein said mammal is an animal.
 38. The method of claims 26 whereinthe compound of formula I and the antibiotic are concomitantlyadministered.
 39. The method of claims 26 wherein the compound offormula I and the antibiotics are concurrently administered.
 40. Acomposition comprising: (a) a pharmaceutically effective amount of thecompound of formula I as shown in claim 1 or a pharmaceuticallyeffective salt thereof; (b) a pharmaceutically effective amount of oneor more antibiotics or a pharmaceutically effective salt thereof; and(c) a pharmaceutically acceptable carrier.
 41. The composition of claim40 wherein the antibiotic is Amikacin, Gentamicin, Spectinomycin,Tobramycin, Imipenem, Meropenem, Cefadroxil, Cefazolin, Cephalexin,Cefaclor, Cefotetan, Cefoxitin, Cefprozil, Cefuroxime, Loracarbef,Cefdinir, Cefixime, Cefoperazone, Cefotaxime, Cefpodoxime, Ceftazidime,Ceftibuten, Ceftozoxime, Ceftriaxone, Cefepime, Azithromycin,Clarithromycin, Dirithromycin, Penicillin G, Cloxacillin, Dicloxacillin,Nafcillin, Oxacillin, Amoxicillin, Ampicillin, Mezlocillin,Piperacillin, Nalidixic Acid, Ciprofloxacin, Enoxacin, Lomefloxacin,Norfloxacin, Ofloxacin, Levofloxacin, Sparfloxacin, Alatrofloxacin,Gatifloxacin, Moxifloxacin, Trimethoprim, Sulfisoxazole,Sulfamethoxazole, Doxycycline, Minocycline, Tetracycline, Aztreonam,Chloramphenicol, Clindamycin, Quinupristin, Fosfomycin, Metronidazole,Nitrofurantoin, Rifampin, Trimethoprim, and Vancomycin.
 42. A method forpreparing a compound of formula I,

which comprises reacting a compound of formula II,

with O-(3,3-diphenylpropyl)difuoroethanethioate in a protic or aproticpolar solvent, or mixtures thereof, at a temperature in a range about 5°C.-100° C.; wherein X is N or CH; R² and R³ are independently H or F; Yis —SO—, —SO₂—, or —SONR⁴—; and R⁴ is —H or —C₁₋₄alkyl.
 43. The metnodof claim 42 wherein the solvent is methanol, acetonitrile, dioxane,methylene chloride, N,N-dimethylformamide, dimethylsulfoxide or alike,or mixtures thereof.
 44. The method of claim 42 wherein the temperatureis in a range about 20° C.-75° C.